9-aminoacridine derivatives possessing psychotropic, antiamnestic and lipid-regulative activity

ABSTRACT

&#34;Derivatives of 9-aminoacridine characterized by psychothropic, antiamnestic and lipid-regulating activities&#34;. 
     New chemical compounds derived of 9-aminoacridine with a general formula are presented: ##STR1## where R=H or CH 3  R 1  =H, CH 3 , or Br 
     R 2  =H, CH 3   
     R 3  =--C 1  -C 5  alkyl phenylmethyl, substituted phenylmethyl or diethylaminoethyl 
     X=C=O, or CHOH, Y=CH 2  or 
     X+Y=CH=CH 
     and their salts with organic and inorganic acids. 
     The target compounds were obtained by a reaction of substituted nitriles of anthranilic acid with dimedone and subsequent cyclization of intermediate enaminonitriles to the corresponding 9-amino-3,4-dihydroacridine-1(2H)-ones. The reduction of the compounds or their alkylated or aralkylated at 9-aminogroupe derivatives results in corresponding alkanols, which on dehydratation give 9-amino-3,4-dihydroacridines. 
     In animal experiments the derivatives of 9-aminoacridine in question showed psychothropic, antiamnestic and lipid-regulating activities and less toxicity as compared with known reference drugs.

This application is a continuation of Ser. No. 08/211,127 filed Jan. 7, 1993 now abandoned which is a 371 of PCT/RU92/00096 filed May 6, 1992.

TECHNICAL FIELD

The development refers to new chemical compounds, particularly to the derivatives of 9-aminoacridine, which show psychotropic, antiamnestic and lipid-regulative activity and may be used in medical practice to treat psychic diseases, in particular senile dementia of Alzheimer's type, as well as diseases connected with disturbances of lipid metabolism.

PRIOR ART

The drug tactine (Summers W. K. et all.//New Engl. J. med. 1986, Vol. 315, No. 20, p. 1241) is widely used abroad in Alzheimer's disease clinics; a new original drug amiridine has been developed at National Research Center for Biologically Active Compounds (USSR Patent Application N 4076765 from 01.07.86. A61K 31/47; U.S. Pat. No. 4,735,953, cl. 514,313, 1988; BRD Patent N 3231571, A 61K 31/47,1988). ##STR2##

The drawbacks of the above drugs are their comparatively high toxicity, side effects of cholinergic nature (tremor, diarrhea, salivation), and toxic effect of tactine on liver.

Derivatives of 9-aminoacridines having a general formula ##STR3## with a structure similar to that of claimed compounds and possessing psychotropic and memory stimulative activity are known (European Patent Application N 0179383 C07D 219/10, -1985; Shutske G. M. et al.//J. Med. Chem. -1989, 32, 1805-1813; Shutske G. M. et al.//J. Med. Chem. -1988, 31, 1279-1282).

Shortcoming of these compounds is a comparatively high toxicity and as a consequence of this--a low therapeutic index.

Structure analogues of the claimed compounds having a formula are known (European Patent Application N 0371388, C07D 219/10, -1990) ##STR4## where ##STR5## which are inhibitors of acetylcholinesterase; however, there is no information on their antiamnestic and lipid-regulative activity.

DETAILED DESCRIPTION OF THE INVENTION

Derivatives of 9-aminoacridine represented by the formula ##STR6## where R=H or CH R1=H,CH3 or Br

R2=H or CH3

R3=C₁ -C₅ alkyl, arylmethyl or, diethylaminoethyl X=C=O or CHOH

Y=CH₂ or

X+Y=CH=CH

and their pharmaceutically acceptable acid addition salts are disclosed.

The preparation of the compounds is performed following the scheme ##STR7##

The compounds having the formula V-VII are prepared by interaction of the corresponding substituted nitrile of aminoanthranilic acid I with dimedone II and subsequent cyclization of the hydrochloride of the substituted 2- (5,5-dimethyl-5-oxocyclohex-1-enyl) amino! benzonitrile III thus obtained into substituted 9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-ones IV; alkylation of compounds IV with aryl- or arylalkylhalogenides into 9-alkyl(arylakyl)-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-ones V; reduction of the compounds IV and V into 9-alkyl(arylalkyl) amino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ols VI; dehydratation of the compounds VI into 9-alkyl(arylalkyl)amino-3,3-dimethyl-3,4-dihydroacridines VII.

The invention is illustrated with following examples.

EXAMPLE 1

2- 5,5-dimethyl-3-oxocyclohex-1-enyl)amino!benzonitrile hydrochloride (IIIa)

6 ml of concentrated hydrochloric acid were added to a solution of 4.72 g (0.04 mol) of anthrsnilonitrile (Ia) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 12 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/3 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 9.1 g (82%) of IIIa, m.p. 214-215 (i-PrOH).

EXAMPLE 2

2- (5,5-dimethyl-3-oxocyclohex-1-enyl)amino!-3,6-dimethyl-benzonitrile hydrochloride (IIId)

6 ml of concentrated hydrochloric acid were added to a solution of 5.84 g (0.04 mol) of 3,6-dimethylanthranilonitrile (Ib) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 14 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/4 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 10.5 g (87%) of IIId, m.p. 208-209 (i-PrOH).

Compounds IIIc-g (Table 1) were prepared in an analogous manner.

EXAMPLE 3

9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H )-one (IVa)

To a Suspension of 27.7 g (0.1 mol) of enamine hydrochloride IIIa in 200 ml of dry THF 27.6 g (0.2 mol) of K₂ O₃ powder and 0.5 g CuCl were added, the mixture was heated under reflux with stirring for 5 h, the hot solution was filtered, the precipitate on the filter was washed with water and dried- Organic mother liquor was evaporated to 1/5 of the original volume, the precipitate was filtered off, washed with water, dried and combined with the former precipitate. Recrystallization from aqueous EtOH gave 21.4 g (89%) of IVa, m.p. 223-224.

EXAMPLE 4

9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one (IVa)

To a suspension of 27.7 g (0.1 mol) of enamine hydrochloride IIIa in 300 ml of dry dioxane 27.6 g (0.2 mol) of K₂ CO₃ powder and 0.5 g CuBr were added, the mixture was heated under reflux with stirring for 5 h, the precipitate was filtered off, washed with water and dried. Organic mother liquor was evaporated to 1/5 of the original volume, the precipitate was filtered off, washed with water, dried and combined with the former precipitate. Recrystallization from aqueous EtOH gave 21.8 g (91%) of IVa, m.p. 223-224.

Compounds IVc-1 (Table 2) were prepared in an analogous manner.

EXAMPLE 5

9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one (Va).

To a solution of 4.8 g (0.02 mol) of the amine IVa in 70 ml of dry DMSO 2.8 g (0.05 mol) of KOH powder were added, the mixture was stirred for 1 h, then 0.8-1 ml of benzyl chloride was added, the solution was allowed to stand overnight, then poured into 350 ml of water, stirred for 0.5 h, left to stand for a day, the precipitate was filtered off, washed with water, dried and recrystallized from aqueous EtOH to give 5.8 g (88%) of Va, m.p. 169-170.

Compounds Vb-3-(Table 2) were prepared in an analogous manner.

EXAMPLE 6

9-benzylamino-3,3-dimethyl-3,4-dihydro acridine-1(2H)-one (Va).

The mixture of 2.4 g (0.01 mol) of the amine IVa, 1.4 g (0.011 mol, 1.27 ml) of benzyl chloride, 0.5 g of Bu₄ NB_(r), 75 ml of CH2C12 and 50 ml of 50% aqueous NaOH was vigorously stirred for 20 h, then poured into 200 ml of ice water, an organic phase was separated, the aqueous phase was extracted with chloroform, (4×50 ml), combined extracts were evaporated, the residue was recrystallized from aqueous EtOH to give 5.8 g (88%) of Va, m.p. 169-170.

Compounds Vo (Table 2) were prepared in an analogous manner.

EXAMPLE 7

9-benzylamino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ol (VIe).

To a suspension of 3.3 g (0.01 mol) of a in 80 ml of absolute THF 0.42 g (0.011 mol) of lithium aluminium hydride was added at 0-5, the mixture was stirred for 2 h under nitrogen current at the same temperatur.e, au excess of lithium aluminium hydride was decomposed by subsequent adding of saturated solution of ammonoum chloride and 30% aqueous potassium hydroxide. An organic phase was separated, the solvent was evaporated, the residue was recrystallized from aqueous EtOH to give 3.2 g (96%) of VIe, m.p. 175-176.

Compounds VIa-d,f-j (Table 3) were prepared in an analogous manner.

EXAMPLE 8

9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one hydrochloride (VIIe).

The solution of 3.32 g (0.01 mol) of VIe in a mixture of 40 ml of EtOH and 5 ml of concentrated HCl was heated under reflux for 1 h. The solvent was evaporated, the residue was recrystallized from aqueous EtOH to give 3.36 g (98%) of VIIe, m.p. 236-237.

Compounds VIIa-d (Table 4) were prepared in an analogous manner

Psychoneurotropic activity of the declared compounds and their influence on learning and memory were observed using unbred male (18-20 g) mice and 180-200 g) rats, held at standard conditions (room temperature 21°-22° C., 12-hours lighting schedule, food and water ad libitum).

All the compounds in question underwent the following tests:

Acute toxicity was studied by the method of Kerber with intra peritoneal drug injection.

Psychotropic activity test included the influence of drugs on animal behavior, motor activity, on the effects of hexenal (30 and 60 mg/kg), arecoline 925 mg/kg, and apomorphine (2 mg/kg). The drugs were applied intraperitoneally in the dose of 1/2o of LD. 6 mice were in the each experimental group.

Step-down test was used to study the influence of drugs on learning and memory in mice using the model of amnesia achieved by the injection of the central ACh-receptors inhibitor scopolamine (Sc).

                                      TABLE I                                      __________________________________________________________________________     2- (5,5-Dimethyl-3oxocyclohex-1-enyl)amino!benzonitriles                       __________________________________________________________________________     III                                                                            W              M.p. IR spectrum                                                                            Found, %                                           n/n                                                                               R  R.sup.1                                                                           R.sup.2                                                                           HX °C.                                                                          ν, sm.sup.-1                                                                        C  H  N  Cl                                        1  2  3  4  5  6    7       8  9  10 11                                        __________________________________________________________________________     Wa H  H  H  HCl                                                                               214-215                                                                             2800-2400,2230                                                                         65,10                                                                             6,40                                                                               9,68                                                                             12,76                                                         1680,1575,1550                                                                 1480                                                       WB H  H  H  -- 187-188                                                                             3230,3150,3090,                                                                        74,57                                                                             6,94                                                                              11,70                                                            3060,3030,2230                                                                 1590,1570,1520                                                                 1475                                                       Wc H  Br H  HCl                                                                               >250 2800-2400,2230                                                                         50,23                                                                             4,80                                                                               7,37                                                                              9,89                                                         1600,1550,1515                                             Wd CH.sub.3                                                                          H  CH.sub.3                                                                          HCl                                                                               208-209                                                                             3150,2800-2400                                                                         67,36                                                                             7,16                                                                              9,2                                                                               11,42                                                         2220,1605,1570,                                                                1530                                                       We H  CH.sub.3                                                                          CH.sub.3                                                                          HCl                                                                               239-241                                                                             2800-2400,2220                                                                         67,42                                                                             7,11                                                                               8,67                                                                             11,49                                                         1600,1530,1515                                             Wf H  CH.sub.3                                                                          H  HCl                                                                               209-210                                                                             2800-2400,2220                                                                         65,77                                                                             6,62                                                                               9,78                                                                             11,90                                                         1595,1560                                                  Wg H  H  CH.sub.3                                                                          HCl                                                                               207-208                                                                             3130,2800-2400                                                                         66,29                                                                             6,62                                                                               9,71                                                                             11,72                                     __________________________________________________________________________                                     reaction                                                          Calculated, %                                                                               time,                                                                              Yield,                                               Empirical Formula                                                                       C  H  N   Cl h   %                                                    12       13 14 15  16 17  18                                         __________________________________________________________________________               C.sub.15 H.sub.16 N.sub.2 O.HCl                                                         65,10                                                                             6.19                                                                              10,12                                                                              12,81                                                                             2   93                                                   C.sub.15 H.sub.16 N.sub.2 O                                                             74,97                                                                             6,71                                                                              11,66                                                           C.sub.15 H.sub.15 BrN.sub.2 O.HCl                                                       50,66                                                                             4,54                                                                              7,88                                                                                9,97                                                                             5   87                                                   C.sub.17 H.sub.20 N.sub.2 O.HCl                                                         66,99                                                                             6,95                                                                              9,19                                                                               11,63                                                                             14  87                                                   C.sub.17 H.sub.20 N.sub.2 O.HCl                                                         66,99                                                                             6,95                                                                              9,19                                                                               11,63                                                                             14  89                                                   C.sub.16 H.sub.18 N.sub.2 O.HCl                                                         66,09                                                                             6,59                                                                              9,63                                                                               12,19                                                                             5   98                                                   C.sub.16 H.sub.18 N.sub.2 O.HCl                                                         66,09                                                                             6,59                                                                              9,63                                                                               12,19                                                                             21  73                                         __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________     9-Amino-3,3-dimethyldihydroacridine-1(2H)-ones V                               __________________________________________________________________________                                  M.p., IR spectrum                                 n/n                                                                               R  R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                               HX        °C.                                                                           sm.sup.-1                                   1  2  3  4  5      6         7     8                                           __________________________________________________________________________     1ya                                                                               H  H  H  H      --        223-224                                                                              3285, 3110, 3060,                                                              1630, 1615, 1605,                                                              1560, 1540                                  1yb                                                                               H  H  H  H      HCl       >300  3320, 3230, 3060,                                                              2670, 2710, 1630,                                                              1570, 1530                                  1yc                                                                               H  B  H  H      --        247-248                                                                              3330, 3180, 1640,                                                              1610, 1595, 1555,                                                              1530                                        1yd                                                                               H  B  H  H      HCl       >280  3200, 3070, 2700,                                                              1650, 1620, 1570,                                                              1530                                        1ye                                                                               CH.sub.3                                                                          H  CH.sub.3                                                                          H      --        142-143                                                                              3450, 3180, 1630,                                                              1600, 1570, 1540                            1yf                                                                               CH.sub.3                                                                          H  CH.sub.3                                                                          H      HCl       208-209                                                                              3250, 3130, 1630,                                                              1580, 1560, 1540                            1yg                                                                               H  CH.sub.3                                                                          CH.sub.3                                                                          H      --        168-170                                                                              3350, 3260, 3240,                                                              3200, 3070, 1630,                                                              1615, 1570, 1540                            1yh                                                                               H  CH.sub.3                                                                          CH.sub.3                                                                          H      HCl       >270  3270, 3075, 2720,                                                              1630, 1570, 1530                            1yi                                                                               H  CH.sub.3                                                                          H  H      --        244-245                                                                              3330, 3270, 3180,                                                              1640, 1610, 1570,                                                              1530                                        1yj                                                                               H  CH.sub.3                                                                          H  H      HCl       >280  3350, 3250, 3110,                                                              2720, 1630, 1570,                                                              1540                                        1yk                                                                               H  H  CH.sub.3                                                                          H      --        174-175                                                                              3400, 3270, 3210,                                                              1610, 1605, 1570,                                                              1550                                        1yl                                                                               H  H  CH.sub.3                                                                          H      HCl       >280  3350, 3230, 1640,                                                              1570, 1530                                  ya H  H  H  C.sub.6 H.sub.5 CH.sub.2                                                              --        169-170                                                                              3030, 1605, 1580,                                                              1570, 1560, 1520                            yb H  H  H  C.sub.6 H.sub.5 CH.sub.2                                                              HCl       231-233                                                                              3350, 2730, 2600,                                                              2360, 1850, 1820,                                                              1640, 1625, 1605,                                                              1530                                        yc H  H  H  2,4-(CH.sub.3).sub.2                                                                  --        130-132                                                                              3500-3100, 1620,                                        C.sub.6 H.sub.3 CH.sub.2                                                                              1580, 1560, 1520                            __________________________________________________________________________     Found       Empirical    Calculated, %                                                                              Yield,                                    C   H   N   Formula      C   H   N   %                                         9   10  11  12           13  14  15  16                                        __________________________________________________________________________     75,35                                                                              7,02                                                                               11,66                                                                              C.sub.15 H.sub.16 N.sub.2 O                                                                 74,97                                                                              6,71                                                                               11,66                                                                              96                                        64,96                                                                              6,59                                                                                9,71                                                                              C.sub.15 H.sub.16 N.sub.2 O.HCl                                                             65,10                                                                              6,19                                                                               10,12                                                                              90                                        56,38                                                                              4,30                                                                                8,47                                                                              C.sub.15 H.sub.15 BrN.sub.2 O                                                               56,44                                                                              4,74                                                                                8,78                                                                              23                                        50,17                                                                              4,64                                                                                7,99                                                                              C.sub.15 H.sub.15 BrN.sub.2 O.HCl                                                           50,66                                                                              4,54                                                                                7,88                                                                              96                                        76,11                                                                              7,42                                                                               10,35                                                                              C.sub.17 H.sub.20 N.sub.2 O                                                                 76,09                                                                              7,51                                                                               10,44                                                                              85                                        67,43                                                                              7,16                                                                                8,70                                                                              C.sub.17 H.sub.20 N.sub.2 O.HCl                                                             66,99                                                                              6,95                                                                               11,63                                                                              97                                        75,71                                                                              7,30                                                                               10,21                                                                              C.sub.17 H.sub.20 N.sub.2 O                                                                 76,09                                                                              7,51                                                                               10,44                                                                              99                                        66,61                                                                              6,60                                                                                8,70                                                                              C.sub.17 H.sub.20 N.sub.2 O.HCl                                                             66,99                                                                              6,95                                                                                9,19                                                                              94                                        75,09                                                                              6,95                                                                               10,84                                                                              C.sub.16 H.sub.18 N.sub.2 O                                                                 75,56                                                                              7,13                                                                               11,02                                                                              98                                        65,88                                                                              6,58                                                                                9,61                                                                              C.sub.16 H.sub.18 N.sub.2 O.HCl                                                             66,09                                                                              6,59                                                                                9,63                                                                              92                                        75,67                                                                              7,24                                                                               11,06                                                                              C.sub.16 H.sub.18 N.sub.2 O                                                                 75,56                                                                              7,13                                                                               11,02                                                                              97                                        65,77                                                                              6,33                                                                                9,30                                                                              C.sub.16 H.sub.18 N.sub.2 O.HCl                                                             66,09                                                                              6,59                                                                                9,63                                                                              94                                        80,21                                                                              6,80                                                                                8,23                                                                              C.sub.22 H.sub.22 N.sub.2 O                                                                 79,95                                                                              6,71                                                                                8,48                                                                              88                                                                             36                                        71,62                                                                              6,52                                                                               10,08                                                                              C.sub.22 H.sub.22 N.sub.2 O.HCl                                                             72,02                                                                              6,32                                                                                7,64                                                                              94                                        80,73                                                                              7,56                                                                                7,50                                                                              C.sub.24 H.sub.26 N.sub.2 O                                                                 80,41                                                                              7,31                                                                                7,81                                                                              75                                        __________________________________________________________________________     1  2  3  4  5      6         7     8                                           __________________________________________________________________________     yd H  H  H  2,4-(CH.sub.3).sub.2                                                                  (Z)-(CHCOOH).sub.2                                                                       163-165                                                                              3400, 3200, 2660,                                       C.sub.6 H.sub.3 CH.sub.2                                                                              1900, 1700, 1640,                                                              1620, 1595, 1530                            ye H  H  H  4-ClC.sub.6 H.sub.4 CH.sub.2                                                          --        144-145                                                                              3400, 3200, 1615,                                                              1585, 1560, 1525                            yf H  H  H  4-ClC.sub.6 H.sub.4 CH.sub.2                                                          HCl       247   3360, 2600, 2450,                                                              2350, 1850, 1650,                                                              1630, 1610, 1590,                                                              1580, 1530                                  yg H  H  H  CH.sub.3                                                                              --        119-120                                                                              3200, 3120, 1615,                                                              1580, 1570, 1530                            yh H  H  H  CH.sub.3                                                                              HCl.0,5H.sub.2 O                                                                         261-262                                                                              3480, 3430, 3250,                                                              3150, 2600, 1800,                                                              1630, 1615, 1600,                                                              1550                                        yi H  H  H  C.sub.2 H.sub.5                                                                       --        145-146                                                                              3350, 3190, 3060,                                                              1605, 1585, 1570,                                                              1525                                        yj H  H  H  C.sub.2 H.sub.5                                                                       HCl.H.sub.2 O                                                                            236-237                                                                              3500, 3430, 2600,                                                              1630, 1620, 1600,                                                              1580, 1530                                  yk H  H  H  C.sub.3 H.sub.7                                                                       --         87-88                                                                               1615, 1595, 1570,                                                              1530                                        yl H  H  H  C.sub.3 H.sub.7                                                                       HCl.0,5H.sub.2 O                                                                         205-206                                                                              3500, 3430, 3260,                                                              3150, 2730, 2540,                                                              1830, 1630, 1615,                                                              1600, 1530                                  ym H  H  H  30-C.sub.3 H.sub.7                                                                    --         84-85                                                                               3350, 1615, 1600,                                                              1570, 1530                                  yn H  H  H  30-C.sub.3 H.sub.7                                                                    HCl.0,5H.sub.2 O                                                                         240-241                                                                              3500, 3430, 3370,                                                              3270, 3200, 2660,                                                              1700, 1630, 1605,                                                              1530                                        yo H  H  H  C.sub.4 H.sub.9                                                                       --         87-88                                                                               1625, 1610, 1600                                                               1570, 1530                                  yp H  H  H  C.sub.4 H.sub.9                                                                       HCl.H.sub.2 O                                                                            220-221                                                                              3520, 3450, 2370,                                                              3270, 3200, 2660,                                                              1700, 1630, 1605,                                                              1530                                        yq H  H  H  30-C.sub.4 H.sub.9                                                                    HCl.0,5H.sub.2 O                                                                         240-241                                                                              3500, 3430, 3370,                                                              3270, 3200, 2660,                                                              1700, 1630, 1605,                                                              1530                                        yr H  H  H  (C.sub.2 H.sub.5).sub.2 N                                                             2HCl      264-265                                                                              3250, 3150, 2600,                                       CH.sub.2 CH.sub.2      2430, 1830, 1690,                                                              1640, 1620, 1590,                                                              1540                                        __________________________________________________________________________     9   10  11  12           13  14  15  16                                        __________________________________________________________________________     70,71                                                                              6,50    C.sub.24 H.sub.26 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                         70,87                                                                              6,37    78                                        72,48                                                                              5,97                                                                                7,99                                                                              C.sub.22 H.sub.21 ClN.sub.2 O                                                               72,42                                                                              5,80                                                                                7,68                                                                              96                                        66,32                                                                              5,96                                                                                6,98                                                                              C.sub.22 H.sub.21 ClN.sub.2 O.HCl                                                           65,84                                                                              5,53                                                                                6,98                                         75,68                                                                              7,47                                                                               10,66                                                                              C.sub.16 H.sub.18 N.sub.2 O                                                                 75,56                                                                              7,13                                                                               11,01                                                                              76                                        64,20                                                                              6,81                                                                                9,20                                                                              C.sub.16 H.sub.18 N.sub.2 O.HCl.                                                            64,10                                                                              6,72                                                                                9,34                                                                              88                                                    .0,5H.sub.2 O                                                      75,82                                                                              7,38                                                                               10,79                                                                              C.sub.17 H.sub.20 N.sub.2 O                                                                 76,09                                                                              7,51                                                                               10,44                                                                              91                                        63,56                                                                              7,26                                                                                8,43                                                                              C.sub.17 H.sub.20 N.sub.2 O.HCl.H.sub.2 O                                                   63,25                                                                              7,18                                                                                8,68                                                                              90                                        76,12                                                                              8,25                                                                                9,69                                                                              C.sub.18 H.sub.22 N.sub.2 O                                                                 76,56                                                                              7,85                                                                                9,92                                                                              45                                        66,27                                                                              7,60                                                                                8,61                                                                              C.sub.18 H.sub.22 N.sub.2 O.HCl.                                                            65,94                                                                              7,38                                                                                8,54                                                                              92                                                    .0,5H.sub.2 O                                                      76,75                                                                              7,67                                                                                9,59                                                                              C.sub.18 H.sub.22 N.sub.2 O                                                                 76,56                                                                              7,85                                                                                9,92                                                                              62                                        66,29                                                                              7,64                                                                                8,25                                                                              C.sub.18 H.sub.22 N.sub.2 O.HCl.                                                            65,94                                                                              7,38                                                                                8,54                                                                              89                                                    .0,5H.sub.2 O                                                      77,45                                                                              8,37                                                                                9,79                                                                              C.sub.19 H.sub.24 N.sub.2 O                                                                 76,99                                                                              8,16                                                                                9,45                                                                              74                                                                             35                                        65,37                                                                              8,15                                                                                8,15                                                                              C.sub.19 H.sub.24 N.sub.2 O.HCl.H.sub.2 O                                                   65,04                                                                              7,36                                                                                7,98                                                                              83                                        66,29                                                                              7,64                                                                                8,25                                                                              C.sub.19 H.sub.24 N.sub.2 O.HCl.                                                            65,94                                                                              7,38                                                                                8,54                                                                              88                                                    .0,5H.sub.2 O                                                      61,49                                                                              7,80                                                                                9,71                                                                              C.sub.21 H.sub.29 N.sub.3 O.2HCl                                                            61,16                                                                              7,58                                                                               10,19                                                                              28                                        __________________________________________________________________________     1  2  3  4  5      6         7     8                                           __________________________________________________________________________     ys H  H  H  C.sub.4 H.sub.9                                                                       (Z)-CHCOOH).sub.2                                                                        156-157                                                                              3400, 2650, 1850,                                                              1640, 1620, 1600,                                                              1540                                        yt H  H  H  C.sub.4 H.sub.9                                                                       HOOCCH.sub.2 CH.sub.2 COOH                                                               111-113                                                                              2700-2400, 1920,                                                               1700, 1650, 1620,                                                              1600, 1540                                  yu H  H  H  C.sub.4 H.sub.9                                                                       2-HOC.sub.6 H.sub.4 COOH                                                                 129-130                                                                              2550, 1930, 1660,                                                              1640, 1620, 1600,                                                              1570, 1540                                  yv H  H  H  C.sub.4 H.sub.9                                                                        ##STR8## 224-225                                                                              3170, 3040, 2650, 1930, 1720, 1670,                                            1610, 1530                                  yw H  H  H  C.sub.4 H.sub.9                                                                        ##STR9## 151(pa3π)                                                                         3470, 2600, 1960, 1720, 1650, 1620,                                            1600, 1570, 1540                            yx H  H  H  C.sub.4 H.sub.9                                                                       HOOCCOOH  149-151                                                                              2650, 1900, 1720,                                                              1640, 1620, 1600,                                                              1540                                        yy H  H  H  C.sub.4 H.sub.9                                                                       H.sub.3 PO.sub.4.3H.sub.2 O                                                              225-226                                                                              2650, 2400, 1930,                                                              1640, 1620, 1605,                                                              1535                                        yz H  H  H  C.sub.4 H.sub.9                                                                       H.sub.2 SO.sub.4.H.sub.2 O                                                               178-179                                                                              3370, 3070, 1640,                                                              1620, 1605, 1540                            yaa                                                                               H  H  H  C.sub.4 H.sub.9                                                                       5-NO.sub.2 -2-Cl                                                                         146-147                                                                              2350, 1950, 1660,                                              C.sub.6 H.sub.3 COOH                                                                           1630, 1610, 1540,                                                              1520                                        ybb                                                                               H  H  H  C.sub.5 H.sub.11                                                                      --         72-73                                                                               1620, 1590, 1570,                                                              1520                                        ycc                                                                               H  H  H  C.sub.5 H.sub.11                                                                      HCl       206-208                                                                              2520, 1870, 1630,                                                              1615, 1520                                  __________________________________________________________________________     9   10  11  12           13  14  15  16                                        __________________________________________________________________________     66,57                                                                              6,84    C.sub.19 H.sub.24 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                         66,97                                                                              6,84    89                                        66,28                                                                              7,04    C.sub.19 H.sub.24 N.sub.2 O.C.sub.4 H.sub.6 O.sub.4                                         66,65                                                                              7,30    92                                        71,39                                                                              6,87    C.sub.19 H.sub.24 N.sub.2 O.C.sub.7 H.sub.6 O.sub.3                                         71,87                                                                              6,96    85                                        63,60                                                                              6,44    C.sub.19 H.sub.24 N.sub.2 O.C.sub.5 H.sub.4 N.sub.2 O.sub.4                                 63,70                                                                              6,24    88                                        61,89                                                                              6,90    C.sub.19 H.sub.24 N.sub.2 O.C.sub.6 H.sub.8 O.sub.7                                         61,46                                                                              6,60    93                                        65,75                                                                              6,93    C.sub.19 H.sub.24 N.sub.2 O.C.sub.2 H.sub.2 O.sub.4                                         65,27                                                                              6,78    91                                        50,52                                                                              7,13    C.sub.19 H.sub.24 N.sub.2 O.H.sub.3 PO.sub.4.3H.sub.2                                       50,88                                                                              7,42    76                                        54,93                                                                              6,90    C.sub.19 H.sub.24 N.sub.2 O.H.sub.2 SO.sub.4.H.sub.2 O                                      55,32                                                                              6,84    95                                        62,65                                                                              5,87    C.sub.19 H.sub.24 N.sub.2 O.C.sub.7 H.sub.4 ClNO.sub.4                                      62,71                                                                              5,67    87                                        77,79                                                                              8,70                                                                                8,76                                                                              C.sub.20 H.sub.26 N.sub.2 O                                                                 77,38                                                                              8,44                                                                                9,02                                                                              42                                        69,62                                                                              7,70                                                                                7,60                                                                              C.sub.20 H.sub.26 N.sub.2 O.HCl                                                             69,25                                                                              7,85                                                                                8,08                                                                              91                                        __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________     9-Amino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1ols YI*.sup.)                 __________________________________________________________________________     YI                      M.p.,                                                                               IR spectrum                                       n/n                                                                               R.sup.3  HX          °C.                                                                          ν, sm.sup.-1                                   1  2        3           4    5                                                 __________________________________________________________________________     YIa                                                                               H        --          200-202                                                                             3370,3195,3040,                                                                1645,1585,1575                                    YIB                                                                               H        (Z)-HOOCCH═CHCOOH                                                                      150-152                                                                             3480,3320,3100,                                                                1615,1560,1495                                    YIc                                                                               C.sub.4 H.sub.9                                                                         --          142-143                                                                             3300,3200-2500                                                                 1610,1570,1555                                    YId                                                                               C.sub.4 H.sub.9                                                                         (Z)-HOOCCH═CHCOOH                                                                      133-134                                                                             3240,3150,3100,                                                                3050,2740,2640,                                                                1640,1585,1525                                    YIe                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                --          175-176                                                                             3380,3220,3060,                                                                3040,1610,1580,                                                                1550,1520                                         YIf                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                (Z)-HOOCCH═CHCOOH                                                                      170-171                                                                             3310,2700,1640,                                                                1610,1590,1560,                                                                1530                                              YIg                                                                               4-ClC.sub.6 H.sub.4 CH.sub.2                                                            --          179-180                                                                             3380,3160,1615,                                                                1580,1560                                         YIh                                                                               4-ClC.sub.6 H.sub.4 CH.sub.2                                                            (Z)-HOOCCH═CHCOOH                                                                      171-172                                                                             3260,3090,3040,                                                                2700,1640,1610,                                                                1570,1520                                         YIi                                                                               2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.4 CH.sub.2                                           --          89-90                                                                               3300,3230,3060,                                                                1620,1580,1560,                                                                1510,1495                                         YIj                                                                               2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.4 CH.sub.2                                           (Z)-HOOCCH═CHCOOH                                                                      155  3260,3230,3150,                                                           (pasπ.)                                                                          3090,3040,1680                                                                 1630,1610,1580,                                                                1530                                              __________________________________________________________________________     Found, %            Calculated, %                                                                               Yield,                                        C  H  N   Empirical Formula                                                                        C   H   N    %                                             6  7  8   9         10  11  12   13                                            __________________________________________________________________________     74.37                                                                             7,89                                                                              11,45                                                                              C.sub.15 H.sub.18 N.sub.2 O                                                              74,35                                                                              7,49                                                                               11,56                                                                               87                                            64.15                                                                             6,63                                                                              7,78                                                                               C.sub.15 H.sub.18 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                      63,67                                                                              6,19                                                                               7,82 93                                            76.57                                                                             9,08                                                                              9,40                                                                               C.sub.19 H.sub.26 N.sub.2 O                                                              76,47                                                                              8,78                                                                               9,39 96                                            66.65                                                                             7,65                                                                              6,53                                                                               C.sub.19 H.sub.26 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                      66,65                                                                              7,30                                                                               6,76 89                                            79.54                                                                             7,41                                                                              8,02                                                                               C.sub.22 H.sub.24 N.sub.2 O                                                              79,48                                                                              7,28                                                                               8,43 96                                            69,54                                                                             6,48                                                                              6,34                                                                               C.sub.22 H.sub.24 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                      69,63                                                                              6,29                                                                               6,25 82                                            71,78                                                                             6,48                                                                              7,69                                                                               C.sub.22 H.sub.23 ClN.sub.2 O                                                            72,02                                                                              6,32                                                                               7,64 95                                            64,88                                                                             5,80                                                                              5,71                                                                               C.sub.22 H.sub.23 ClN.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                    64,66                                                                              5,64                                                                               5,80 87                                            79,61                                                                             8,28                                                                              7,30                                                                               C.sub.24 H.sub.28 N.sub.2 O                                                              79,96                                                                              7,83                                                                               7,77 93                                            70,66                                                                             7,12                                                                              5,64                                                                               C.sub.24 H.sub.28 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                                      70,57                                                                              6,77                                                                               5,88 86                                            __________________________________________________________________________      *.sup.) R═R.sup.1 ═R.sup.2 ═H                                

                                      TABLE 4                                      __________________________________________________________________________     9-Amino-3,3-dimethyl-3,4-dihydroacridines.sup.y11*)                            __________________________________________________________________________                            M.p. IR spectrum                                        n/n                                                                               R.sup.3                                                                               HX           °C.                                                                          v, sm.sup.-1                                       1  2      3            4    5                                                  __________________________________________________________________________     y11a                                                                              H      --           154-155                                                                             3320, 3140, 1645,                                                              1570                                               y11b                                                                              H      HCl          300  3330, 3170, 2760,                                                              1650, 1630, 1590,                                                              1560, 1540                                         y11c                                                                              C.sub.4 H.sub.9                                                                       HCl          192-193                                                                             3240, 2710, 2650,                                                              1630, 1620, 1610,                                                              1560, 1530                                         y11d                                                                              4-ClC.sub.6 H.sub.4 CH.sub.2                                                          HCl          222-223                                                                             3230, 3100, 2730,                                                              1630, 1620, 1600,                                                              1545, 1525                                         y11e                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              HCl          236-237                                                                             3190, 3100, 3060,                                                              3030, 2720, 1625,                                                              1600, 1550                                         y11f                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              HOOCCH.sub.2 CH.sub.2 COOH                                                                   93-94                                                                              3340, 2600, 1920,                                                              1720, 1710, 1650,                                                              1620, 1570, 1660,                                                              1540                                               y11g                                                                              C.sub.6 H.sub.5 CH.sub.2                                                               ##STR10##   137-138                                                                             3250, 2550                                         y11h                                                                              C.sub.6 H.sub.5 CH.sub.2                                                               ##STR11##   151-152                                                                             3220, 2550, 1940, 1650, 1620, 1570, 1550,                                      1530                                               y11i                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              2-HOC.sub.6 H.sub.4 COOH                                                                    134-135                                                                             3250, 3060, 2650,                                                              1940, 1620, 1605,                                                              1580, 1550                                         y11j                                                                              C.sub.6 H.sub.5 CH.sub.2                                                               ##STR12##   220-221                                                                             3280, 3130, 2600, 1940, 1705, 1670, 1650,                                      1630, 1610, 1570, 1530                             y11k                                                                              C.sub.6 H.sub.5 CH.sub.2                                                               ##STR13##   104-105                                                                             3430, 3375, 2620, 2040, 1950, 1670, 1650,                                      1630, 1570, 1560, 1525                             __________________________________________________________________________     Found, %  Empirical   Calculated, %                                                                            Yield,                                         C  H   N  Formula     C  H   N  %                                              6  7   8  9           10 11  12 13                                             __________________________________________________________________________     80,15                                                                             7,05                                                                               12,31                                                                             C.sub.15 H.sub.16 N.sub.2                                                                  80,32                                                                             7,19                                                                               12,49                                                                             98                                             68,71                                                                             6,58                                                                               10,51                                                                             C.sub.15 H.sub.16 N.sub.2.HCl                                                              69,09                                                                             6,57                                                                               10,74                                                                             96                                             71,96                                                                             7,95                                                                                8,53                                                                             C.sub.19 H.sub.24 N.sub.2.HCl                                                              72,02                                                                             7,95                                                                                8,84                                                                             95                                             68,74                                                                             5,44                                                                                7,45                                                                             C.sub.22 H.sub.21 ClN.sub.2.HCl                                                            68,57                                                                             5,76                                                                                7,27                                                                             96                                             75,06                                                                             6,64                                                                                7,62                                                                             C.sub.22 H.sub.22 N.sub.2.HCl                                                              75,31                                                                             6,61                                                                                7,98                                                                             96                                             72,03                                                                             6,88   C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.6 O.sub.4                                          72,20                                                                             6,52   99                                             76,87                                                                             6,10   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.5 NO.sub.2                                         76,86                                                                             6,22   90                                             76,42                                                                             6,60   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.5 NO.sub.2                                         76,86                                                                             6,22   82                                             76,58                                                                             6,12   C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.6 O.sub.3                                          76,97                                                                             6,24   83                                             69,02                                                                             5,91   C.sub.22 H.sub.22 N.sub.2.C.sub.5 H.sub.4 N.sub.2 O.sub.4                                  68,92                                                                             5,57   98                                             65,98                                                                             6,32   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.8 O.sub.7                                          66,39                                                                             5,97   99                                             __________________________________________________________________________     1  2      3            4    5                                                  __________________________________________________________________________     y11l                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              C.sub.6 H.sub.5 COOH                                                                        128-129                                                                             3220, 2400, 1950,                                                              1650, 1620, 1570,                                                              1530                                               y11m                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              C.sub.6 H.sub.5 CH.sub.2 COOH                                                               103-104                                                                             3230, 2500, 1920,                                                              1650, 1620, 1570,                                                              1550, 1525                                         y11n                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              4-HOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 COOH.                                                 122-123                                                                             3550, 3230, 2660,                                            .H.sub.2 O        2600, 1940, 1650,                                                              1610, 1570, 1540                                   y11o                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              HOOCCOOH: 0,5H.sub.2 O                                                                      191-192                                                                             3320, 3100-2500,                                                               1920, 1720, 1690,                                                              1630, 1620, 1590,                                                              1580, 1550, 1520                                   y11p                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              HOOCCH.sub.2 COOH                                                                           130-131                                                                             3280, 2600, 1950,                                                         (pa3π.)                                                                          1620, 1560, 1530                                   y11q                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              H.sub.3 PO.sub.4.3H.sub.2 O                                                                 234-235                                                                             3280, 3100-2600,                                                               2400, 1630, 1620,                                                              1600, 1570, 1525                                   y11r                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              H.sub.2 SO.sub.4.1,5H.sub.2 O                                                               161-162                                                                             3280-3000,                                                                     2700-2400, 1630,                                                               1620, 1600, 1570,                                                              1530                                               y11s                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              5-NO.sub.2 -2-ClC.sub.6 H.sub.3 COOH                                                        200-21                                                                              3250, 2700-2400,                                                               1950, 1660, 1620,                                                              1610, 1570, 1515                                   y11t                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 C(O)NHCH.sub.2 COOH                                                                137-138                                                                             3340, 3260,                                                                    2700-2400; 1980,                                                               1660, 1630, 1590,                                                              1560                                               y11u                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              (Z)-HOOCCHCHCOOH                                                                            146-147                                                                             3270, 2650, 1900,                                                              1680, 1640, 1610,                                                              1570, 1530                                         __________________________________________________________________________     6  7   8  9           10 11  12 13                                             __________________________________________________________________________     79,80                                                                              6,43  C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.6 O.sub.2                                          79,79                                                                             6,46   92                                             79,52                                                                              6,78  C.sub.22 H.sub.22 N.sub.2 C.sub.8 H.sub.8 O.sub.2                                          79,97                                                                             6,71   85                                             74,76                                                                              7,11  C.sub.22 H.sub.22 N.sub.2.C.sub.9 H.sub.10 O.sub.3.                                        74,67                                                                             6,87   86                                                       .H.sub.2 O                                                           69,60                                                                              6,21  C.sub.22 H.sub.22 N.sub.2.C.sub.2 H.sub.2 O.sub.4.                                         69,72                                                                             6,09   81                                                       .0,5H.sub.2 O                                                        72,08                                                                              6,60  C.sub.22 H.sub.22 N.sub.2.C.sub.3 H.sub.4 O.sub.4                                          71,75                                                                             6,26   68                                             56,48                                                                              6,45  C.sub.22 H.sub.22 N.sub.2.H.sub.3 PO.sub.4.3H.sub.2 O                                      56,55                                                                             6,70   95                                             60,07                                                                              6,36  C.sub.22 H.sub.22 N.sub.2.H.sub.2 SO.sub.4.                                                60,11                                                                             6,19   86                                                       .1,5H.sub.2 O                                                        67,25                                                                              5,19  C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.4 ClNO.sub.4                                       67,50                                                                             5,08   92                                             72,04                                                                              6,48  C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.7 NO.sub.3                                         72,37                                                                             6,77   96                                             72,15                                                                              6,22  C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.4 O.sub.4                                          72,54                                                                             6,09   98                                             __________________________________________________________________________      .sup.*) R = R.sup.1 = R.sup.2 = H                                        

The influence of drugs on reflex conditioning in rats was studied by the passive avoidance test in conditions of 50% acquisition. The effect of the compound was estimated by the increase of the relative number of learned animals with respect to that of control group. The test substances were injected intraperitoneally 20 min before training in the dose of 0.1 mg/kg, at dose the reference drug amiridine was effective in the passive avoidance test. The other reference drug--noothropic agent piracetam--was given in the dose 250 mg/kg 60 min before training. Amnestic syndrome was stimulated by 20 days application of Sc at the daily dose of 1 mg/kg intraperitoneally. To assess the autiamnestic effects of the claimed compounds, the compounds and the reference drugs they were applied in the course of 10 days immediately following cancellation of scopolamine injection. The passive avoidance test was performed within 24 hours after the last application of test preparations.

Contractile activity of isolated smooth muscle organs (guinea-pig ilium, rat testicles) under the action of test substances was studied by the method of Blattner with the use of ACh and adrenaline.

Acetylcholinesterase inhibition under the action of preparations was assessed by the spectrophotometric technique of Ellman on the enzyme from human erythrocytes.

Ionic permeabilities of excitable membranes under the action of drugs were studied by the voltage clamp technique in the Ranvier node of the frog.

Microviscosity of membranes of brain synaptosomes was studied with the use of molecular probe pirren. Brain tissue homogenization and preparation of synaptosomes were performed by the method of De Robertis.

Since the substances in question are the derivatives of aminoacridine, tacrine has been also used as a reference drug along with amiridine and piracetam.

The results of the study of pharmacological activity of substances in question are summarized in Table 5. All the substances can be attributed to the class of moderately and low toxic ones since LD varied in the limits of 40-1000 mg/kg being greater than 100 mg/kg in the main group of substances which is a substantial advantage with respect to reference drugs amiridine and tactine having LD 35 and 52 mg/kg, respectively.

The main group of substances increased moter activity by 40-90. Test substances magnified the effect of arecoline by 30-66% indicating to the involvement of cholinergic mechanisms in their pharmacological activity, through their ability to inhibit acetylcholinesterase was less pronounced than that of the reference drugs. They did not effect the contractile activity of smooth muscles in contrast to amiridine. Therefore their side effects of cholinergic origin (tremor, salivation, diarrea) are less expressed in comparison with reference drug and were observed only at toxic doses. There was no substautial influence of test preparations on the effects of hexenal and apomorphine.

As revealed by passive avoidance test most of the substances (IVf, Vd, Vu, VIk, VIIb, VIId, VIIe, VIIi, VIII, VIIo, VIIp, VIIq, and VIIr) statistically significantly improved performance of normal rats, the substances Vd, VIId, VIIe being as effective in improving learning and memory as amiridine and piracetam. However they have an advantage over amiridine as being of low toxicity.

The results of the Step-down test with scopolamine induced amnesia in mice are presented in Table 6. The substances VIIe, Vp, VIIb, VIIi, and Vaa showed pronounced antiatonestic activity, comparable with that of amiridine and tacrine.

The therapeutic effects of amiridine and tactine are commonly attributed to their ability to block potassium permeability and to inhibit acetylcholinesterase. However the data of Table 6 suggest that the drugs antiamnestic activity is most closely related to their ability to induce the shift of potassium permeability activation region to the hyperpolarizing values of membrane potential. In vivo conditions this effect may be tantamount to the increase of resting membrane potential of nerve cells thus providing more safe generation of action potential especially in nerve cells with decreased excitability. The effect may provide a new approach in the search for drugs with antiamnestic activity.

                                      TABLE 5                                      __________________________________________________________________________     Pharmacological effects of aminoacridine derivatives                                                     Increase of dura-                                                  Acetylcho-                                                                           Motor acti-                                                                          tion of arecoline                                                                      Increase of the number                          Substance                                                                           LD.sub.50                                                                            linesterase                                                                          vity incre-                                                                          induced hyper-                                                                         of correct trails (% to                         designa-                                                                            (mg/kg)                                                                              inhibition                                                                           ment (% to                                                                           kynesis (% to                                                                          control). Passive                            No.                                                                               tion by Kerber                                                                            IC.sub.50 (M)                                                                        control)                                                                             control)                                                                               avoidance test (rats)                        1  2    3     4     5     6       7                                            __________________________________________________________________________     1. IVb  70.0 ± 4.3                                                                        3.5 · 10.sup.-6                                                              0     33*    30                                           2. IVd  >500  5.0 · 10.sup.-5                                                             15    20       0                                           3. IVf  40.0 ± 1.2                                                                        1.3 · 10.sup.-5                                                              0     0       0                                           4. IVh   >500 3.0 · 10.sup.-5                                                              0    20       0                                           5. IVl  616.7 ± 23.7                                                                      6.3 · 10.sup.-7                                                              57*   0       0                                           6. IVj  63.6 ± 8.7                                                                        3.0 · 10.sup.-5                                                              0     30*     0                                           7. Vb   735.0 ± 21.8                                                                      no effect                                                                             80*  15      25                                           8. Vd   >1000 1.0 · 10.sup.-5                                                              90*   0       50*                                         9. Vf   >1000 8.0 · 10.sup.-5                                                             13     0       0                                           10.                                                                               Vh   65.8 ± 4.8                                                                        4.0 · 10.sup.-7                                                              40*  20       0                                              Vj   73.3 ± 8.6                                                                        1.7 · 10.sup.-6                                                              59*  20       0                                              Vl   283.3 ± 35.7                                                                      3.0 · 10.sup.-6                                                              74*   30*     0                                              Vn   70.2 ± 7.3                                                                        6.0 · 10.sup.-6                                                              76*   0       0                                              Vp   200.0 ± 21.9                                                                      2.5 · 10.sup.-5                                                              69*   0      25                                              Vq   158.3 ± 21.9                                                                      2.0 · 10.sup.-6                                                              75*   0       0                                              Vr   135.0 ± 8.2                                                                       5.0 · 10.sup.-5                                                              0    26       0                                              Vs   165.8 ± 14.8                                                                      7.0 · 10.sup.-6                                                              0     0      15                                              Vt   210.0 ± 9.8                                                                       7.0 · 10.sup.-6                                                              0     0       0                                              Vu   210.0 ± 5.8                                                                       6.0 · 10.sup.-6                                                             20     0       30*                                         20.                                                                               Vv   433.3 ± 7.8                                                                       7.0 · 10.sup.-6                                                             26    15      25                                              Vw   125.0 ± 11.8                                                                      7.0 · 10.sup.-6                                                             10    10      10                                              Vx   121.7 ± 15.5                                                                      1.0 · 10.sup.-5                                                              0     0      25                                              Vy   210.0 ± 14.8                                                                      7.0 · 10.sup.-6                                                              0     0       0                                              Vz   200.0 ± 21.9                                                                      7.0 · 10.sup.-6                                                              0     0      20                                              Vaa  650.0 ± 11.3                                                                      7.0 · 10.sup.-6                                                             26    25      15                                              VIb  63.3 ± 8.8                                                                        1.2 · 10.sup.-6                                                              40*   66*    20                                              VIg  80.0 ± 2.7                                                                        0.3 · 10.sup.-5                                                              40*   36*     0                                              VIi  75.0 ± 1.2                                                                        1.0 · 10.sup.-6                                                             13     46*    15                                              VIj  33.4 ± 3.2                                                                        2.5 · 10.sup.-6                                                              55*  13       40*                                         30.                                                                               VIe  50.0 ± 8.6                                                                        1.3 · 10.sup.-6                                                              64*  15       0                                              VIIb 37.5 ± 0.9                                                                        7.5 · 10.sup.-8                                                              41*  25       40*                                            VIIc 33.3 ± 4.4                                                                        0.6 · 10.sup.-6                                                             20    15      25                                              VIId 125.8 ± 8.9                                                                       0.6 · 10.sup.-8                                                             28    15       60*                                            VIIe 158.3 ± 21.9                                                                      1.2 · 10.sup.-6                                                             32    12       50*                                            VIIu 83.8 ± 5.6                                                                        2.3 · 10.sup.-6                                                             15    12       0                                              VIIf 125.0 ± 15.5                                                                      6.1 · 10.sup.-6                                                              0     0       0                                              VIIg 200.0 ± 21.9                                                                      5.0 · 10.sup.-7                                                             23     0       0                                              VIIh 116.7 ± 10.9                                                                      5.0 · 10.sup.-7                                                             13    28      20                                              VIIi   500 1.0 · 10.sup.-6                                                             20    15       35*                                         40.                                                                               VIIk 90.5 ± 8.                                                                         2.0 · 10.sup.-6                                                             20    20      25                                              VIIl 116.7 ± 10.9                                                                      8.0 · 10.sup.-7                                                             10    15       40*                                            VIIm 112.5 ± 10.9                                                                      2.7 · 10.sup.-6                                                             15    15      25                                              VIIn 125.0 ± 10.9                                                                      6.3 · 10.sup.-7                                                             11     46*    40                                              VIIo 62.5 ± 7.7                                                                        2.5 · 10.sup.-6                                                             16     0       40*                                            VIIp 75.0 ± 3.8                                                                        8.5 · 10.sup.-7                                                             33    21       45*                                            VIIq 73.3 ± 4.4                                                                        6.3 · 10.sup.-7                                                             20     30*     45*                                            VIIr 69.5 ± 5.6                                                                        8.5 · 10.sup.-7                                                              0     0       45*                                            Amiridine                                                                           52.0 ± 3.4                                                                        1.5 · 10.sup.-7                                                              45*  100*     70*                                            Tacrine                                                                             35.5 ± 1.8                                                                        3.8 · 10.sup.-7                                                              0     88*    25                                           50.                                                                               Piracetam                                                                            1000 no effect                                                                             0     0       63*                                         __________________________________________________________________________      *  statistically significant, p < 0.05                                   

                  TABLE 6                                                          ______________________________________                                         Antiamnestic activity and some physiological effect                            of new aminoacridine derivatives                                                                                  The shift of acti-                                                             vation region of                                   Antiamnestic                K channels                                         activity in                 Substance lowest                                   Step-down test       AChE   concentrations                                     (% of mice Block of  inhi-  in M. producing                             Sub-   with latency >                                                                            K -channels                                                                              bition measureable                                 stance cut off)   IC (M)    IC (M) shift of 1-2 mV                             ______________________________________                                         VIIe   25         1 10      1.2 10 <10                                         VIb    0          1 10      1.2 10 <10                                         Vf     0          5 10      8.0 10 no effect                                   Vp     25         1 10      2.5 10 <10                                         IVb    0          no effect 3.5 10 no effect                                   VIId   20         1 10      6.0 10 <10                                         Vd     20         1 10      1.0 10 <10                                         VIIb   25         no effect 7.5 10 <10                                         VIj    0          1 10      3.0 10 no effect                                   VIi    0          1 10      1.0 10 no effect                                   Vb     0          1 10      no effect                                                                             no effect                                   VIIi   25         3 10      1.0 10 <10                                         Vaa    25         5 10      7.0 10 <10                                         Tacrine                                                                               33         5 10      3.5 10 <10                                         Amiridine                                                                             33         5 10      1.5 10 <10                                         ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                         Antiamnestic activity of substance Vp in                                       rats on the model of amnestic syndrome                                         Drug,                                                                          duration of                     Microviscosity                                 application                                                                              Dose      Passive avoidance                                                                          changes in % to                                (in days) (mg/kg)   latency (sec)                                                                              control                                        ______________________________________                                         Control   --        160.0 + 12.4                                                                               100                                            Scopolamine (Sc)                                                                         1          70.4 + 10.5*                                                                              131.2*                                         20 + 10 (saline)                                                               Sc + Vp   1 + 1     170.3 + 14.9.sup.x                                                                         93.8                                           20 + 10                                                                        Sc + amiridine                                                                           1 + 1     149.0 + 11.7.sup.x                                                                         105.0.sup.x                                    20 + 10                                                                        Sc + tacrine                                                                             1 + 1     169.0 + 14.8                                                                               97.2.sup.x                                     20 + 10                                                                        Sc + piracetam                                                                            1 + 250  162.3 + 13.3.sup.x                                                                         102.6.sup.x                                    20 + 10                                                                        ______________________________________                                          *p < 0.05 with respect to control group                                        .sup.x p < 0.05 with respect to scopolamine group                        

                  TABLE 8                                                          ______________________________________                                         Antiamnestic activity of Vp substance                                          in old rats                                                                                                        Cholesterol                                                            Micro-  content in                                 Drug,           Passive avoidance                                                                          viscosity                                                                              synaptosomes                               duration of     latency in 7                                                                               changes (% from                                    application                                                                            Dose    days after  (% to con-                                                                             total lipid                                (in days)                                                                              (mg/kg) training (sec)                                                                             trol)   content)                                   ______________________________________                                         Control I                                                                              --      109.6 + 24.7                                                                               100     28.2 + 2.2                                 (3 month)                                                                      Control II                                                                             --       47.5 + 13.3*                                                                              132*    39.6 + 0.7*                                (18 month)                                                                     Vp      1       169.4 + 10.5.sup.x                                                                          97.9.sup.x                                                                            30.1 + 2.4.sup.x                           (20)                                                                           Amiridine                                                                              1       116.1 + 16.9.sup.x+                                                                        101.7.sup.x                                                                            33.2 + 0.8.sup.x                           (20)                                                                           Tacrine 1       163.4 + 16.5.sup.x                                                                         101.4.sup.x                                                                            39.7 + 1.4*                                (20)                                                                           Piracetam                                                                              250     120.0 + 24.3*.sup.+                                                                        101.8.sup.x                                                                            35.1 + 1.0*                                (20)                                                                           ______________________________________                                          *  p < 0.05 with respect to control I                                          .sup.x - p < 0.05 with respect to control II                                   .sup.+  - p < 0.05 with respect to Vp group                              

For more detailed study the substance Vp was chosen because of its most pronounced capability to induce the shift of potassium permeability voltage dependency and substautial amnestic activity with lower toxicity (LD=200-22 mg/kg) thau that of amiridine and tactine. On the model of atonestic syndrome induced by multiple scopolamine injection substance Vo improved performance in passive avoidance test in the 10 days application course to the level achieved under the treatment with reference drugs (Table 7). The improvement of reflex conditioning was accompanied by the normalizing of microviscosity of brain synaptosomes increased in the animals with amnestic syndrome.

Table 8 illustrates the data obtained with the use of old rats. 20 days course of treatment with substance Vp improved performance of old rats (age 18 months) in passive avoidance test more significantly than in 6 month old adult rats, while the reference drugs improved the learning and memory only to the level achieved in 6 month old rats. Improvement of animal performance was accompanied by the normalizing of brain synaptosomes microviscosity under the action of all the substances tested. In addition to that amiridine and substance Vp normalized the cholesterol content of brain synaptosomes. The latter observation indicates to the possible interference of amiridine and substance Vo into the processes of atherogenesis in old animals.

Lipid regulative activity of the declared compounds--derivatives of 9-amino acridine--were evaluated in vitro--were evaluated in vitro using rat adipocytes. Adipocytes were separated from adipose tissue of testis appendages of adult male rats. Lipid composition analysis was performed by the method of thin-layer chromatography.

Quantitative analysis of phospholipids (PL), mono- and diacylglycerides (MDG), triacylglycerides (TG), free fatty acids (FFA), free cholesterol (FCL), and methyl esters of fatty acids (MEFA) was performed by the method of spectrophotometry.

The results Of studies of lipid-regulative activity of the declared compounds and probucol--the drug widely used to treat atherosclerosis (Duckley M. M. - T., Goa K. L., Price A. H., Bfogden R. N. Drugs, 1989, 37, 761-800) are presented in Tables 9-13.

Compounds VIIe, Vo and VIId possess the most potent effect on lipid composition of adipocytes (in absolute parameters and in relations of separate fractions).

Compound VIIe. Under the effect of this compound in adipocytes phospholipids content increase and simultaneous decrease of triglycerides content takes place (Table 9). The content of methyl esters of fatty acids is decreased. Increase of PL/TG ratio (Table 11) probably takes place not only at the expense of lipid synthesis in cells (Tables 10, 12) but also due to ejection of triacylglycerides into the external medium with simultaneous retention of phospholipids in a cell (Tables 10, 12, 13). A tendency towards increase of relative cholesterol ejection from a cell is observed (Table 10, 12).

                  TABLE 9                                                          ______________________________________                                         Lipid composition of adiposytes (%) after incubation in the                    presence of the compounds of the aminoacridine series.                         PL - phospholipids, CL - cholesterol, FFA - free fatty acids,                  TG - triglycerides, MEFA - methyl esher of fatty acids.                        Compounds                                                                              PL       CL       FFA    TG     MEFA                                   ______________________________________                                         control 15,5-0,5 21,3-0,6 22,2-0,3                                                                              23,5-0,4                                                                              18,9-0,6                               ethanol 14,8-0,6 21,0-0,5 21,1-0,5                                                                              24,1-0,5                                                                              18,7-0,7                               VIIe    21,5-2,3 22,6-1,7 20,3-0,6                                                                              20,3-1,9                                                                              15,3-1,6                               VIj     18,1-1,7 22,5-1,0 23,0-0,8                                                                              21,2-1,3                                                                              15,2-0,6                               Vp      19,1-1,0 22,9-1,9 22,1-0,9                                                                              21,5-1,9                                                                              14,2-0,9                               VIId    15,5-2,6 22,4-1,0 24,5-0,7                                                                              21,2-1,3                                                                              15,7-0,8                               Vaa     14,1-0,5 22,3-1,3 22,8-0,6                                                                              24,2-0,7                                                                              16,6-0,8                               VIIi    18,5-1,2 22,2-0,4 21,4-0,5                                                                              21,4-0,2                                                                              16,4-0,7                               VIIj    13,9-1,7 22,8-0,9 22,4-2,4                                                                              24,1-0,6                                                                              16,8-0,6                               VIIk    17,0-1,8 22,8-2,2 21,8-1,8                                                                              21,8-1,4                                                                              16,7-2,8                               probucol                                                                               15,5-0,6 18,3-1,3 24,3-0,6                                                                              22,6-1,1                                                                              19,1-1,3                               ______________________________________                                          n = 19 for control and ethanol. In all the rest cases n = 3.                   *statistically reliable differences (in comparison with ethanol), p <          0,05.                                                                    

                  TABLE 10                                                         ______________________________________                                         Lipid content (%) in incubation medium after incubation of                     adipocytes in the presence of the compounds of aminoacridine series.           PL - phospholipids, MDG - mono- and diglycerides, CL -                         cholesterol, FFA - free fatty acids, TG - triglycerides.                       Compounds                                                                              PL       MDG        CL   FFA    TG                                     ______________________________________                                         control 15,3-0,5 18,5-0,5 19,0-0,3                                                                              23,1-0,5                                                                              23,9-0,5                               ethanol 15,9-0,5 17,8-0,6 19,7-0,5                                                                              23,0-0,7                                                                              23,2-0,5                               VIIe    14,9-1,5 15,3-2,3 20,3-1,5                                                                              24,1-1,5                                                                              25,3-1,1                               VIj     14,6-2,1 15,3-0,9 22,3-1,1*                                                                             24,2-1,4                                                                              23,4-1,4                               Vp      13,5-0,9 16,0-0,7 20,9-1,2                                                                              23,7-1,1                                                                              25,8-1,5                               VIId    16,0-0,6 16,1-0,7 21,2-0,7                                                                              22,8-0,8                                                                              23,7-0,3                               Vaa     13,5-0,4 20,4-2,8 18,8-0,6                                                                              22,6-1,5                                                                              24,6-1,4                               VIIi    17,2-1,3 19,2-2,8 19,4-0,8                                                                              23,1-2,8                                                                              21,1-1,6                               VIIj    17,9-0,3 18,6-1,4 18,7-0,3                                                                              23,5-2,1                                                                              21,3-0,5                               VIIk    17,5-1,6 17,9-1,8 19,2-1,0                                                                              22,6-1,0                                                                              22,7-0,8                               ______________________________________                                          n = 19 for control, n = 18 for ethanol. In all the rest cases n = 3.           *statistically reliable differences (in comparison with ethanol), p <          0,05.                                                                    

                  TABLE 11                                                         ______________________________________                                         Relation of various functions of lipids in adipocytes after                    incubation of cells in the presence of compounds of                            aminoacridine series.                                                          Symbols - see Table 9.                                                         Compound   FFA/TG       PL/TG   PL/CL                                          ______________________________________                                         control    0.94         0.67    0.73                                           ethanol    0.88.sup.+   0.61    0.70                                           VIIe       1.00         1.06    0.95*                                          VIj        1.08         0.85    0.80                                           Vp         1.03         0.89    0.83*                                          VIId       1.16*        0.73    0.69                                           Vaa        0.94         0.58    0.63                                           VIIj       1.00         0.86    0.83                                           VIIk       0.93         0.58    0.61                                           VIIl       1.00         0.78    0.75                                           probucol   1.10*        0.69    0.84*                                          ______________________________________                                          n = 19 for control and ethanol. In all the rest cases n = 3.                   *  p < 0.05 in comparison with "ethanol" group.                                .sup.+ - p < 0.05 in comparison with control.                            

                  TABLE 12                                                         ______________________________________                                         Relations of separate functions of lipids in incubation                        medium after incubation of adipocytes in the presence of                       aminoacridine derivatives.                                                     Symbols - see Table 9.                                                         Compound   FFA/TG       PL/TG   PL/CL                                          ______________________________________                                         control    0.97         0.64    0.80                                           ethanol    0.99         0.68    0.81                                           VIIe       0.95         0.59    0.73                                           VIj        1.03         0.62    0.65                                           Vp         0.92         0.52    0.65                                           VIId       0.96         0.67    0.75                                           Vaa        0.92         0.55    0.71                                           VIIj       1.07         0.81    0.89                                           VIIk       1.10         0.84    0.96                                           VIIl       1.00         0.77    0.91                                           ______________________________________                                    

                  TABLE 13                                                         ______________________________________                                         Distribution of separate lipids between cells and incubation                   medium after incubation of adipocytes in the presence of                       compounds of aminoacridine series.                                             cells. index "m" le 9. Index "c"                                               incubation medium.                                                             Compound       PLc/PLm  FFAc/FFAm                                              ______________________________________                                         control        1.01     0.96                                                   ethanol        0.93     0.92                                                   VIIe           1.44*    0.84                                                   VIj            1.24*    0.95                                                   Vp             1.41*    0.93                                                   VIId           0.97     1.07*                                                  Vaa            1.04     1.01                                                   VIIj           1.08     0.93                                                   VIIk           0.78     0.95                                                   VIIl           0.97     0.96                                                   ______________________________________                                          n = 19 for control and ethanol.                                                In all the rest cases n = 3.                                                   *  p < 0.05.                                                             

Compound Vo. This compound is aualogous to VIIe according to the effect on lipid composition of adipocytes. Accumulation of phospholipids in a cell (Tables 9, 11, 13), enhanced ejection of triacylglycerides into external medium (Tables 10, 12) and sharp decreases in the content of methyl ester of fatty acids (Table 9) are observed.

Compound VIId. This compound has a significaut lipolytic effect, which is proved by an increase of content of fatty acids in a cell (Table 9) and a sharp increase of FFA/TG relation in favor of fatty acids (Table 11).

The performed studies prove the fact, that the declared compounds have an effect on lipid cell composition. Compounds VIIe, Vo and VIId show the most potent effect. The other studied compounds also influence the lipid content. A combin&tion of the described properties of the three mentioned compounds permits consideration of them as the most promising from the point of view of the development of new drugs to treat diseases connected with lipid metabolism disorders. The compounds VIIe and Vo which increase PL/TG relations and decrease cell cholesterol level, may be recommended for the study as potential anti-atherosclerotic drugs and compounds to prevent adipose degeneration of organs. Compound VIId due to its significant lipolytic effect may be considered as a drug to treat diseases accompanied by obesity. Compounds Vp and VIId are not inferior of the most effective drug in world-wide clinical practice--probucol, and compound VIIe supresses it.

In summary, the proposed derivatives of 9-aminoacridine have a lower toxicity thau known drugs (tacrine, amiridine) have antiamnestic activity, they are effective in comparative or lower doses ensuring a wider therapeutic range of activity of the given compounds. An additional valuable property of these compounds is lipid-regulative activity, which proves perspectiveness of mentioned compounds as anti-atherosclerotic drugs and drugs to treat diseases accompanied by lipid metabolism disorders, and in particular phospholipids (obesity, diabetes mellitus, and membronopathy of various genesis). 

We claim:
 1. Compounds of the formula ##STR14## where R=H or CH₃ ; R¹ =H, CH₃ or Br;R² =H or CH₃ ; R³ =C₁ -C₅ alkyl, diethylaminoethyl, phenylmethyl, or substituted phenylmethyl wherein the substituents of the phenyl group are Cl or CH₃ ; X=C=O or CHOH, Y=CH₂ or X+Y=CH=CH and their pharmaceutically acceptable acid addition salts, thereof showing psychotropic, antiamnestic and lipid-regulative activity. 